The candidate proposes to undertake a program of research that will involve extensive training in molecular biology, neuroanatomy and, functional genomics, complementing the candidate's thorough training in electrophysiology. This project will focus on obtaining a better understanding of the developmental processes governing adult neurogenesis. Neural stem cells give rise to new neurons throughout an individual's lifetime, but they only reside within a few privileged regions of the brain (e.g. subgranular zone of dentate gyrus). Harnessing the therapeutic potential of these cells remains a promise unfulfilled, because neural stem cells simply do not function properly when transplanted into regions other than those that normally support adult neurogenesis (e.g. dentate gyrus). In order to overcome this limitation we need an improved understanding how the neural stem cell's microenvironment differs from that of other brain regions that do not support neurogenesis. Wnt signaling is a component of the adult dentate gyrus microenvironment that plays a critical role in embryonic hippocampal development, but is poorly understood in the adult. Our initial studies suggest that canonical Wnts (e.g. Wnt1) promote maintenance of proliferative, multipotential adult hippocampal precursors (AHPs) while the non-canonical class of Wnts (e.g. Wnt5a) induces cell-cycle exit and differentiation into neurons. This proposal will test the role of different Wnt signals on the development of adult hippocampal precursors in vitro. The proposed research will begin to validate this model by addressing the following aims: (1) Determine if and how Wnt governs proliferation versus differentiation of Adult Hippocampal Precursors (AHPs) in vitro; (2) Determine functional role of AHP derived Wnt in vitro; (3) Determine how Wnt5a induces neuronal differentiation The candidate's background of graduate study in neuroscience and clinical training in psychiatry is particularly well suited to make basic science discoveries and apply them in areas of clinical relevance. Using a broad molecular approach to the study adult neural precursor development, the candidate hopes to understand what drives neurogenesis in certain brain regions and not others. In the long term, he believes that this knowledge will provide the information necessary to transform non-neurogenic regions of the brain into regions more hospitable to developing progenitor cells. This will pave the way for effective neural stem cell transplants. The mentor Daniel Geschwind M.D., Ph.D., is also a physician scientist and serves as an ideal role model for excellence in research. The environment of the UCLA School of Medicine as a whole, in particular the Geschwind lab, the Center for Neurogenetics and UCLA Stem Cell Institute, is ideally suited in both physical plant and intellectual resources to embark upon these studies. Lastly, in addition to acquiring new skills the candidate will be active in a variety of scientific venues (journal clubs, national meetings) and the Department of Psychiatry, all preparing for a career in academic medicine with both research and clinical responsibilities. [unreadable] [unreadable]